scholarly journals Molecular Genetic Basis of Hypertrophic Cardiomyopathy

2021 ◽  
Vol 128 (10) ◽  
pp. 1533-1553
Author(s):  
A.J. Marian
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Phenotypic Expression ◽  
Left Ventricular ◽  
Clinical Effects ◽  
Genes Encoding ◽  
Large Families ◽  
Encoding Protein

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. MYH7 and MYBPC3 , encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.

scholarly journals An Unusual Presentation of a Myocardial Crypt in Hypertrophic Cardiomyopathy

2014 ◽  
Vol 2014 ◽  
pp. 1-3
Author(s):  
Danny A. J. P. van de Sande ◽  
Jan Hoogsteen ◽  
Luc J. H. J. Theunissen
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Interventricular Septum ◽  
Positive Family History ◽  
Phenotypic Expression ◽  
Anterior Wall ◽  
Left Ventricular ◽  
Genes Encoding ◽  
History Of ◽  
Basal Septum ◽  
Myocardial Crypts

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease with prevalence of 0.2% in the population. More than 1000 mutations in more than 10 genes encoding for proteins of the cardiac sarcomere have been identified. Cardiac magnetic resonance imaging (CMR) is used to characterize left ventricular morphology with great precision in patients with HCM and it identifies unique structural abnormalities in patients with HCM. We present a case of a 56-year-old man who had positive family history of HCM who was a carrier of the genetic MYH-7 2770 G > C, exon 23 mutation. Transthoracic echocardiography showed thickening of the interventricular septum (16 mm) and in particular the basal septum. CMR confirmed the diagnosis of HCM in the anteroseptal myocardium with a thickness of 23 mm and also revealed large and deep myocardial crypts in the anterior wall. These myocardial crypts are rarely found in the so-called genotype positive and phenotype positive patients, as in our case. Also the crypts in this case are deeper and wider than those reported in other cases. So in conclusion, this case reveals an uncommon finding of a myocardial crypt at an unusual myocardial site with the unusual morphology in a patient with genotypic and phenotypic expression of hypertrophic cardiomyopathy.

scholarly journals Genetic Testing in Patients with Hypertrophic Cardiomyopathy

2021 ◽  
Vol 22 (19) ◽  
pp. 10401
Author(s):  
Jiri Bonaventura ◽  
Eva Polakova ◽  
Veronika Vejtasova ◽  
Josef Veselka
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Mendelian Disease ◽  
Sarcomeric Proteins ◽  
Pathogenic Variants ◽  
Large Numbers ◽  
Uncertain Significance ◽  
Common Clinical Practice

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

Hypertrophic cardiomyopathy: genetics

ESC CardioMed ◽  
2018 ◽  
pp. 1443-1450
Author(s):  
Mohammed Majid Akhtar ◽  
Luis Rocha Lopes
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Mapk Pathway ◽  
Glycogen Storage ◽  
Cellular Level ◽  
Causative Mutation ◽  
Clinical Role ◽  
Genes Encoding ◽  
Associated Proteins

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

Cardiovascular genetics: the role of genetic testing in diagnosis and management of patients with hypertrophic cardiomyopathy

Heart ◽  
2020 ◽  
pp. heartjnl-2020-316798
Author(s):  
Monica Ahluwalia ◽  
Carolyn Y Ho
Keyword(s):  
At Risk ◽  
Clinical Practice ◽  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Family Management ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Genetic testing in hypertrophic cardiomyopathy (HCM) is a valuable tool to manage patients and their families. Genetic testing can help inform diagnosis and differentiate HCM from other disorders that also result in increased left ventricular wall thickness, thereby directly impacting treatment. Moreover, genetic testing can definitively identify at-risk relatives and focus family management. Pathogenic variants in sarcomere and sarcomere-related genes have been implicated in causing HCM, and targeted gene panel testing is recommended for patients once a clinical diagnosis has been established. If a pathogenic or likely pathogenic variant is identified in a patient with HCM, predictive genetic testing is recommended for their at-risk relatives to determine who is at risk and to guide longitudinal screening and risk stratification. However, there are important challenges and considerations to implementing genetic testing in clinical practice. Genetic testing results can have psychological and other implications for patients and their families, emphasising the importance of genetic counselling before and after genetic testing. Determining the clinical relevance of genetic testing results is also complex and requires expertise in understanding of human genetic variation and clinical manifestations of the disease. In this review, we discuss the genetics of HCM and how to integrate genetic testing in clinical practice.

Differences in the diagnostic value of various criteria of negative T waves for hypertrophic cardiomyopathy based on a molecular genetic diagnosis

2007 ◽  
Vol 112 (11) ◽  
pp. 577-582 ◽  
Author(s):  
Tetsuo Konno ◽  
Noboru Fujino ◽  
Kenshi Hayashi ◽  
Katsuharu Uchiyama ◽  
Eiichi Masuta ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Diagnostic Value ◽  
Left Ventricular ◽  
Lower Sensitivity ◽  
T Wave ◽  
Accurate Definition ◽  
Definition Of ◽  
T Waves

Differences in the diagnostic value of a variety of definitions of negative T waves for HCM (hypertrophic cardiomyopathy) have not yet been clarified, resulting in a number of definitions being applied in previous studies. The aim of the present study was to determine the most accurate diagnostic definition of negative T waves for HCM in genotyped populations. Electrocardiographic and echocardiographic findings were analysed in 161 genotyped subjects (97 carriers and 64 non-carriers). We applied three different criteria that have been used in previous studies: Criterion 1, negative T wave >10 mm in depth in any leads; Criterion 2, negative T wave >3 mm in depth in at least two leads; and Criterion 3, negative T wave >1 mm in depth in at least two leads. Of the three criteria, Criterion 3 had the highest sensitivity (43% compared with 5 and 26% in Criterion 1 and Criterion 2 respectively; P<0.0001) and retained a specificity of 95%, resulting in the highest accuracy. In comparison with abnormal Q waves, negative T waves for Criterion 3 had a lower sensitivity in detecting carriers without LVH (left ventricular hypertrophy) (12.9% for negative T waves compared with 22.6% for abnormal Q waves). On the other hand, in detecting carriers with LVH, the sensitivity of negative T waves increased in a stepwise direction with the increasing extent of LVH (P<0.001), whereas there was less association between the sensitivity of abnormal Q waves and the extent of LVH. In conclusion, Criterion 3 for negative T waves may be the most accurate definition of HCM based on genetic diagnoses. Negative T waves may show different diagnostic value according to the different criteria and phenotypes in genotyped populations with HCM.

scholarly journals A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Paal Skytt Andersen ◽  
Paula Louise Hedley ◽  
Stephen P. Page ◽  
Petros Syrris ◽  
Johanna Catharina Moolman-Smook ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Late Onset ◽  
Large Family ◽  
Left Ventricular ◽  
Cascade Screening ◽  
Essential Light Chain ◽  
Mutation Carriers ◽  
Genes Encoding ◽  
The Mean

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations inMYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, inMYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion,MYL3mutations can present with low expressivity and late onset.

scholarly journals Silver-Russell syndrome: genetic basis and molecular genetic testing

2010 ◽  
Vol 5 (1) ◽  
Author(s):  
Thomas Eggermann ◽  
Matthias Begemann ◽  
Gerhard Binder ◽  
Sabrina Spengler
Keyword(s):  
Genetic Testing ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Molecular Genetic Testing ◽  
Silver Russell Syndrome

scholarly journals Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 741 ◽  
Author(s):  
Dorsch ◽  
Schuldt ◽  
Remedios ◽  
Schinkel ◽  
Jong ◽  
...  
Keyword(s):  
Quality Control ◽  
Hypertrophic Cardiomyopathy ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Left Ventricular ◽  
Microtubule Network ◽  
Protein Levels ◽  
Tubulin Acetylation ◽  
Genes Encoding ◽  
Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and 5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

scholarly journals Evaluation of genetic causes of cardiomyopathy in childhood

2015 ◽  
Vol 25 (S2) ◽  
pp. 43-50 ◽  
Author(s):  
Stephanie M. Ware
Keyword(s):  
Genetic Testing ◽  
Genetic Basis ◽  
Clinical Care ◽  
Standard Of Care ◽  
Paediatric Population ◽  
Prognostic Information ◽  
Genetic Causes ◽  
Genes Encoding ◽  
Family Based ◽  
High Level

AbstractCardiomyopathy frequently has a genetic basis. In adults, mutations in genes encoding components of the sarcomere, cytoskeleton, or desmosome are frequent genetic causes of cardiomyopathy. Although children share these causes, ~30% of children have an underlying metabolic, syndromic, or neuromuscular condition causing their cardiomyopathy, making the aetiologies more diverse in children as compared with adults. Although some children present with obvious signs or symptoms of metabolic, syndromic, or neuromuscular disease, other cases may be quite subtle, requiring a high level of suspicion in order to diagnose them. In general, the younger the child, the more extensive the differential. Advantages of identifying the underlying genetic cause of cardiomyopathy in the paediatric population include confirming the diagnosis in ambiguous cases, facilitating appropriate surveillance and management of cardiac and extra-cardiac diseases, providing prognostic information, and establishing the genetic basis in the family, thereby allowing the identification of at-risk relatives and institution of appropriate family screening as indicated. For these reasons, genetic testing is increasingly recognised as standard of care, and guidelines for genetic counselling, testing, and incorporation of family-based risk assessment have been established. Therapies aimed at treating specific genetic aetiologies of cardiomyopathy are emerging and are exciting new developments that require increasingly sophisticated approaches to diagnosis. As genetic testing capabilities continue to expand technically, careful interpretation, knowledgeable clinical utilisation, and appropriate dissemination of genetic information are important and challenging components of clinical care.

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